While the recent optimization of ART has prevented AIDS and reduced AIDS-related morbidities and mortality for the majority of HIV-infected individuals, a scalable treatment that can cure HIV infection is still not available. Thus, lifelon administration of ART is necessary, posing significant challenges in terms of costs and clinical safety. Major obstacles to curing HIV infection include (1) persistent immune abnormalities, including inflammation, limited CD4 T cell reconstitution, and functional exhaustion of antiviral T cells; (ii) low levels of viral replication, particularly in tissues, and (iii) the presence of a sall pool of long-lived latently infected cells that are not affected by ART. Importantly, these contributors may be triggering and sustaining each other, thus creating a vicious cycle that maintains HIV persistence during ART. As such, novel approaches aimed at limiting residual inflammation, improving antiviral responses and reducing the survival of infected cells are needed for curing HIV. In this proposal, using the well-established nonhuman primate model of SIV infection, we will explore the effects of Interleukin (IL)-10 blockade on virus persistence in ART-treated, SIV- infected rhesus macaques (RMs). In preliminary work we have shown that IL-10 is a key contributor to HIV persistence by augmenting the survival of infected cells and of activated cells thereby favoring viral dissemination, increasing the expression of immune check point blockers (ICB), known to trigger T cell quiescence and viral latency, and having IL-10 producing B cells at the proximity of Tfh cells, major HIV reservoir. Based on these preliminary results, we propose that administration of an anti-IL-10 blocking antibody (?IL-10) will reduce HIV persistence by: (i) decreasing the survival of infected cells that can seed the HIV reservoir, and (ii) decreasing the expression of molecules known to be upstream regulators of T cell quiescence and HIV latency. In the R21 phase of this project we will administer ?IL-10 to SIV infected cART treated RMs and define a dose that is safe and efficacious as monitored by the impact of the treatment on Tfh survival, germinal center organization, and the expression of ICB. In the R33 phase, once safety and optimal dose of this intervention are established, we will provide mechanistic insights into the positive impact of IL-10 neutralization on germinal center organization, Tfh survival and magnitude of the HIV reservoir. If our hypothesis is correct, we expect that by administration of ?IL-10 in ART-treated, SIV-infected RMs, survival of infected and activated cells will be reduced, and more specifically for Tfh cells. Concomitantly, the persistent SIV reservoir will be progressively reduced. In summary, the proposed work will translate an improved understanding of HIV latency through rigorously controlled in vivo studies of a novel intervention in the most relevant animal model. If successful in inducing progressive reduction of the SIV reservoir, the proposed treatment would ultimately be tested in clinical trial aimed at curing HIV infection.